Pituitary tumors account for 15% of intracranial neoplasms and are benign monoclonal neoplasms which may be clinically silent or secrete hormones including prolactin, growth hormone, ACTH, or rarely TSH or gonadotropins. These adenomas account for clinical infertility, growth disorders and hypercortisolism or metabolic dysfunctions associated with hypo-pituitarism. This proposal is aimed at exploring the role of disordered pituitary cell proliferation control in the pathogenesis of these invariably benign adenomas. In the first Aim, we will study mechanisms underlying pituitary aneuploidy, premature proliferative arrest (senescence), markers of cell proliferation and tumorigenesis in transgenic models of murine pituitary tumors (1GSU.PTTG and Rb heterozygotes). Mechanisms for both genetic and hormonally induced pituitary tumorigenesis will be studied in these genotypes and in pituitary cell cultures. In the second Aim we will study DNA damage, cellular markers of aneuploidy and senescent mediators in human pituitary tumors. In the third Aim we will study mechanisms for Rb/E2F induction of pituitary tumors by assessing E2F1 induction of Pttg transcription and protein expression in Rb mice, in mutant human cancer cells devoid of p53 or p21, as well as in human pituitary adenomas. Results of these experiments will enable further insights into the role of cell cycle control and growth constraint of experimental and human pituitary tumors, underlying their failure to progress to malignancy. The results will improve our understanding of clinical endocrine syndromes associated with infertility, growth disorders, hypercortisolism or adrenal, thyroid and gonadal failure due to abrogated pituitary function. PUBLIC HEALTH RELEVANCE: This project will study growth control of experimental pituitary tumor models, as well as hormone-secreting or clinically non-secreting human pituitary tumors. These experiments will provide insight into mechanisms underlying development of infertility, growth disorders or hypercortisolism, as well as failure of thyroid, adrenal or gonadal function due to disordered pituitary function.